This review memo covers Tetanus Toxoid manufacturing and testing, and ---(b)(4)---- serology validation studies. Areas covered by this review include all information in Sections 2 and 3 that are relevant to the manufacturing and testing of the Tetanus Toxin and Tetanus Toxoid. Additionally, ---(b)(4)---- serology validation studies and (b)(4) protocols in section 5.3.5.4 are reviewed.

Background:

On August 12, 2009 GlaxoSmithKline Biologicals submitted a BLA for Meningococcal Group C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, which has the proposed proprietary name MenHibrix. Clinical development of this vaccine was conducted under IND (b)(4). The vaccine contains N. meningitidis serogroup C and Y polysaccharides (PSC and PSY, respectively) and H. influenzae type b capsular polysaccharide (PRP), with each covalently attached to tetanus toxoid. The final vaccine product is lyophilized and provided in (b)(4) glass vials, and is reconstituted prior to injection with a saline diluent in –b(4)--------. The final vaccine contains 2.5 mg PRP-TT, 5 mg PSC-TT and 5 mg PSY-TT in a 0.5 ml dose. The vaccine is indicated for immunization of toddlers 6 weeks through 15 months for the prevention of invasive disease caused by N. meningitidis serogroup C and Y and H. influenzae type b.

Manufacturing of tetanus toxoid (TT) at the –(b)(4)-- site, from ---------------(b)(4)----------------------------------------- of the purified tetanus toxoid

Purification and --(b)(4)-------of the TT performed at Rixensart, Belgium

TT process development to include manufacturing history at –(b)(4)-- as well as TT lot development in support of MenHibrix

Process Validation of the TT manufacturing process

C. tetani (b)(4) system

Tetanus Toxoid Specifications

Stability studies

---(b)(4)-- serology review (sections 5.3.5.4; -----(b)(4)-----)

1. Manufacture of TT at -(b)(4)-- facility (3.2.S.2.2):

17 pages redacted do to (b)(4)

specifications. Although we understand that these specifications were initially determined for manufacturing in building -(b)(4)-, we recommend that you establish updated Alert and Action limits for monitoring tests throughout the manufacturing process for the purified TT produced in -(b)(4)-. Please provide updated Alert and Action limits for the TT manufacturing process or provide a proposal on how you will revise these specifications in the future. Please specify the number of lots you will use in establishing updated specifications.

4. Please specify the exact date when TT manufacturing was initiated in building -(b)(4)-.

5. We note that the initial -(b)(4)- testing done at Rixensart on the purified TT is for monitoring purposes only (Table 99, m3.2.S.2.4-section 3.2). In order to maintain manufacturing process consistency, we request that you develop a specification ----------(b)(4)------ for the -(b)(4)- analysis on TT prior to ------(b)(4)------------ at Rixensart. In addition, we request that you revise the -(b)(4)- test currently performed on the purified TT----(b)(4)----- to a “quality decision test” instead of a monitoring purposes only test. Please comment.